Our medication development program for cocaine abuse is based on using the acute and chronic withdrawal periods as windows of treatment opportunity. We have previously demonstrated that these periods are characterized by mechanistic flux, during which, not only cocaine ensitization/consolidation take place, but also previously established sensitization and/or progressive ratio cocaine self administration can be reversed with 5-HT3 or 5-HT2A antagonists. The animal data with these antagonists are consistent with clinical data demonstrating that dozapine, a mixed 5-HT3 and 5-HT2 antagonist, substantially reduces stimulant abuse in both schizophrenics and drug abusers. The present proposal emphasizes the use of a non-abused drug (e.g., mazindol or pergolide) to simulate daily acute cocaine withdrawal, which is subsequently targeted with a 5-HT3, 5-HT2A or NMDA antagonists. Mazindol increases both dopamine and 5-HT neurotransmission by uptake inhibition, while pergolide has high agonist affinity at both D2 and 5-HT2A receptors. Our proposed treatment strategy is not only to reverse previously established cocaine sensitization but also to maintain the de-sensitized state and thus facilitate cocaine abstinence. We will rapidly screen putative treatment regimens with locomotor measurement and behavior rating;treatments exhibiting significant efficacy reversing behavioral sensitization will be subsequently examined for reversal of progressive ratio self-administration and neurobiological sensitization markers. Our neurobiological markers include the ones that have been repeatedly demonstrated to be associated with sensitization establishment following chronic cocaine injections and subsequent withdrawal (e.g., NR2B / GluR1 subunit expression, dopamine/glutamate efflux). To the extent that sensitization is involved in recidivism in cocaine abusers, our medication development program provides a road map for treatment intervention that is based not only on specific drugs, but perhaps more importantly, on the treatment dosing regimen. We hypothesize that, when used on a daily basis by human abusers, a combination of non-abused stimulant and an antagonist administered during the ensuing acute withdrawal period may promote long-term maintenance of a desensitized state or abstinence.